PMID- 36467452 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20221206 IS - 2589-5370 (Electronic) IS - 2589-5370 (Linking) VI - 53 DP - 2022 Nov TI - Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial. PG - 101707 LID - 10.1016/j.eclinm.2022.101707 [doi] LID - 101707 AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of motor neurons, and development of effective medicines is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified the Src/c-Abl inhibitor bosutinib, which is approved for the treatment of chronic myelogenous leukemia (CML), as a candidate for the molecular targeted therapy of ALS. METHODS: An open-label, multicentre, dose-escalation phase 1 study using a 3 + 3 design was conducted in 4 hospitals in Japan to evaluate the safety and tolerability of bosutinib in patients with ALS. Furthermore, the exploratory efficacy was evaluated using Revised ALS Functional Rating Scale (ALSFRS-R), predictive biomarkers including plasma neurofilament light chain (NFL) were explored, and single-cell RNA sequencing of iPSC-derived motor neurons was conducted. Patients, whose total ALSFRS-R scores decreased by 1-3 points during the 12-week, received escalating doses starting from 100 mg quaque die (QD) up to 400 mg QD based on dose-limiting toxicity (DLT) occurrence, and all participants who received one dose of the study drug were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT04744532, as Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic Lateral Sclerosis Medicine (iDReAM) study. FINDINGS: Between March 29, 2019 and May 7, 2021, 20 patients were enrolled, 13 of whom received bosutinib treatment and 12 were included in the safety and efficacy analyses. No DLTs were observed up to 300 mg QD, but DLTs were observed in 3/3 patients of the 400 mg QD cohort. In all patients receiving 100 mg-400 mg, the prevalent adverse events (AEs) were gastrointestinal AEs in 12 patients (92.3%), liver function related AEs in 7 patients (53.8%), and rash in 3 patients (23.1%). The safety profile was consistent with that known for CML treatment, and ALS-specific AEs were not observed. A subset of patients (5/9 patients) was found to respond well to bosutinib treatment over the 12-week treatment period. It was found that the treatment-responsive patients could be distinguished by their lower levels of plasma NFL. Furthermore, single-cell RNA sequencing of iPSC-derived motor neurons revealed the pathogenesis related molecular signature in patients with ALS showing responsiveness to bosutinib. INTERPRETATION: This is the first trial of a Src/c-Abl inhibitor, bosutinib, for patients with ALS. The safety and tolerability of bosutinib up to 300 mg, not 400 mg, in ALS were described, and responsiveness of patients on motor function was observed. Since this was an open-label trial within a short period with a limited number of patients, further clinical trials will be required. FUNDING: AMED and iPS Cell Research Fund. CI - (c) 2022 The Author(s). FAU - Imamura, Keiko AU - Imamura K AD - Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. FAU - Izumi, Yuishin AU - Izumi Y AD - Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan. FAU - Nagai, Makiko AU - Nagai M AD - Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan. FAU - Nishiyama, Kazutoshi AU - Nishiyama K AD - Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan. FAU - Watanabe, Yasuhiro AU - Watanabe Y AD - Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan. FAU - Hanajima, Ritsuko AU - Hanajima R AD - Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan. FAU - Egawa, Naohiro AU - Egawa N AD - Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. FAU - Ayaki, Takashi AU - Ayaki T AD - Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. FAU - Oki, Ryosuke AU - Oki R AD - Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan. FAU - Fujita, Koji AU - Fujita K AD - Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan. FAU - Uozumi, Ryuji AU - Uozumi R AD - Department of Biomedical Statistics and Bioinformatics, Kyoto University, Kyoto, Japan. FAU - Morinaga, Akiko AU - Morinaga A AD - Pfizer R&D Japan G.K., Tokyo, Japan. FAU - Hirohashi, Tomoko AU - Hirohashi T AD - Pfizer Inc., New York, New York, USA. FAU - Fujii, Yosuke AU - Fujii Y AD - Pfizer R&D Japan G.K., Tokyo, Japan. FAU - Yamamoto, Takuya AU - Yamamoto T AD - Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. FAU - Tatebe, Harutsugu AU - Tatebe H AD - Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba, Japan. FAU - Tokuda, Takahiko AU - Tokuda T AD - Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba, Japan. FAU - Takahashi, Naoto AU - Takahashi N AD - Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan. FAU - Morita, Satoshi AU - Morita S AD - Department of Biomedical Statistics and Bioinformatics, Kyoto University, Kyoto, Japan. FAU - Takahashi, Ryosuke AU - Takahashi R AD - Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. FAU - Inoue, Haruhisa AU - Inoue H AD - Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. LA - eng SI - ClinicalTrials.gov/NCT04744532 PT - Journal Article DEP - 20221025 PL - England TA - EClinicalMedicine JT - EClinicalMedicine JID - 101733727 PMC - PMC9716331 COIS- RU reports consulting fees from Eisai, Sawai Pharmaceutical, and EP Croit. NT reports speakers bureaus fees from Pfizer, Novartis Pharmaceuticals, and Otsuka Pharmaceutical. RT reports consulting fees from Kan Institute. RT and NT received research funding and honoraria for lectures from Pfizer. The other authors declare that they have no competing interests. EDAT- 2022/12/06 06:00 MHDA- 2022/12/06 06:01 PMCR- 2022/10/25 CRDT- 2022/12/05 04:25 PHST- 2022/08/05 00:00 [received] PHST- 2022/09/29 00:00 [revised] PHST- 2022/09/30 00:00 [accepted] PHST- 2022/12/05 04:25 [entrez] PHST- 2022/12/06 06:00 [pubmed] PHST- 2022/12/06 06:01 [medline] PHST- 2022/10/25 00:00 [pmc-release] AID - S2589-5370(22)00437-0 [pii] AID - 101707 [pii] AID - 10.1016/j.eclinm.2022.101707 [doi] PST - epublish SO - EClinicalMedicine. 2022 Oct 25;53:101707. doi: 10.1016/j.eclinm.2022.101707. eCollection 2022 Nov.